CHAPTER 1.1 LITERATURE REVIEW AND OBJECTIVES
1.1.2 MECHANISM OF ACTION AND EFFICACY OF INJECTABLE PROGESTOGEN CONTRACEPTIVES
1.1.2.2 Efficacy
The progestogen-only injectable contraceptives are demonstrably extremely effective (Mishell etal,1968; Tyler, 1970; Garza-Floresetal, 1992; Kaunitz, 1992; Garza-Flores et al, 1994; Kaunitz, 1994; Kaunitz and Rosenfield, 1994; Lande, 1995; Bigrigg, 1999).
Many clinical trials have investigated the efficacy of these preparations, but most were conducted some time ago, in the 1970s and early 1980s. Efficacy findings are discussed below and a summary of relevant studies is presented in Table 1.1.2.
DMPA Studies
One of the first efficacy studies undertaken on DMPA (150mg given every 3 months) found no pregnancies, even amongst women who reported from one to four weeks late for
their next injection (Mishell et al, 1968). This study was conducted amongst 100 Caucasian women and lasted for one year. Another early collaborative study of 3857 women receiving 150mg of DMP A every three months was conducted between 1965 and 1971. Itset the two year cumulative pregnancy rate for DMPA, calculated by the life table technique, at 0.53 per 100 women after two years (Schwallie and Azenzo, 1973).
The DMPA efficacy findings (pregnancy rate=Oo4 at 15 months) in Chinnatamby's (1971) study were comparable with the efficacy reported in the World Health Organization (WHO) (1983) trial (Table 1.1.2). A recent study, which retrospectively examined contraceptive failures amongst DMPA users, reported to the Insurance Division of the Planned Parenthood Federation of America Inc. from 1994 to 1998, found a crude rate of pregnancy of0042per 1000 women using DMP A in each year (Borgattaetal, 2002).
Overall, in the studies summarized in Table 1.1.2, the failure rates for DMP A were similar.
NET-EN Studies
Banerjeeetal (1984) conducted a large clinical trial (N=2388) on NET-EN, used by Indian women from 16 Human Reproductive Research Centres located in different parts ofIndia, with two dosing schedules (two monthly, and two monthly for six months then three monthly). They reported failure rates at six months of 1.2 per 100 users for the two monthly group, and 0.7 per 100 users from the second dosage regimen" These authors suggested that the unexpectedly high method failure rates in the first six months of use, compared with findings from previous studies, could be due to the lower average body weight of Indian women compared to women from western countries. However, failure rates reported in a field study in six family planning clinics in Bangladesh (Rahmanet al,
4Note: during the first six months the dosage schedule was the same for the two groups.
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1985) were lower than the Indian study (Banerjeeet al, 1984). In this study, Rahman et al (1985) found a cumulative pregnancy rate at 18 months of 0.4 for NET -EN given every 8 weeks for six months and then every 12 weeks. In a study of Mexican women taking NET-EN on a two monthly dosage regimen, the efficacy at 18 months was reported to be 0.3 (Meadeet al, 1984). The NET-EN efficacy findings from the studies summarized in this chapter are less consistent, even within dosage regimens, than the DMP A efficacy findings.
Comparative Studies
One ofthe earliest multi-national clinical trials compared the efficacy ofDMPA (150mg) and NET-EN (200mg), with both preparations given every twelve weeks (World Health Organization, 1977). This study was to have lasted for two years,but was terminated after about one year as the NET-EN pregnancy rate exceeded the allowed maximum. The cumulative pregnancy rate at one year was found to be 0.7for DMPA and 3.6 for Net- EN.Itshould be noted that 75% of all conceptions with NET-EN were estimated to have occurred during the first injection period,that 54% of all pregnancies occurred in only two of the ten centres (Bangkok and Chandigarh), and that efficacy was found to decrease with decreased body weight, as the mean admission body weight of NET-EN users who became pregnant was significantly lower (World Health Organization, 1977). EI- Mahgoub and Karim (1972), in a study of Egyptian women (1968-1971), found no pregnancies with NET-EN given every 84 days, even though, in some instances, delays between injections of95 days were reported. Zanartu and Navarro (1968) in a study in Chile,and Chinnatamby (1971) in a study in Ceylon (now Sri Lanka),reported a pregnancy rate of2.3 per 100 woman-years for NET-EN given every twelve weeks, which is lower than the pregnancy rate recorded in the World Health Organization (1977)
trial. A later WHO multi-national clinical trial (World Health Organization, 1983) of 1587 women given DMPA every 90 days, 789 women given NET-EN every 60 days,and 796 women given NET-EN every60 days for 6 months and then every 84 days,found the cumulative life-table accidental pregnancy rates after two years to be 0.4,0.4 and 1.4 per 100 women respectively.
Reviews
Several reviews of studies on progestogen-only injectable efficacy have been published and the pregnancy rates are reported as follows:
• DMPA 150mg given every 12 weeks/3 months: 0 to 1.2pregnancies per 100 women (Fraser and Weisberg, 1981;Fraser, 1982;Fraser and HoIck, 1983);0.5per 100 woman-years in the largest trials (Fraser and Weisberg, 1981; Fraser,1982); not exceeding 0.5per 100 woman-years at one year Benagiano and Primiero, 1983a); life table failure rate: less than 1.0 per 100 woman-years (Hickey and Fraser, 1995);first- year failure rate in the United States of 0.3% (Lande, 1995); in-use failure rate of 0.0 to 0.7 per 100 woman-years (Kaunitz, 1992; Bigrigget al, 1999;Kaunitz,2000); in taking the mean of all available studies at the time, a 'typical' failure rate of 0.3% (Trussell and Kost, 1987).
• Inan evaluation of five large controlled multi-centre studies, Kaunitz (1992) reported that there were only 24 pregnancies among 7849 women using Depo-Provera for 122496 patient-months.
• Weight and concurrent medication does not affect DMPA efficacy,presumably because of high circulating levels of MPA (Kaunitz, 2000).
• Contraceptive failure ofDMPA with perfect or typical use is <0.3% per year which is comparable with the failure rate of surgical sterilization (Kaunitz,2002)
31
• NET-EN givenevery 8 weeks or 60 days:less than one pregnancy per 100 woman- years at 18 months (World Health Organization 1982); 0.6 per 100 woman-years (Benagiano and Primiero, 1983b).
• NET-EN given 10 weeks after the first injection,and then every 12 weeks;or given every 60 days or 8 weeks for six months and then every 12 weeks:0.7 per 100
woman-years (Benagiano and Primiero, 1983b); less than I per 100 woman-years at 12 months and 1.6at 18 months (World Health Organization 1982).
• NET-EN given every 12 weeks/90 days:3.6per 100 woman-years (World Health Organization, 1982); 1.5 to 5.2 per 100 woman-years (Benagiano and Primiero, 1983b)
• NET-EN (unspecified regimen): 1.0 to 1.5 per 100 woman-years (Fraser, 1982); 0.5 to 1.5 (Bigrigget al, 1999).
• Trussellet al (1990) provide"summ ary estimates of contraceptive failure" and give the lowest expected, and typical percentage,of accidental pregnancies in the United States, during the first year of use, as 0.3 for DMPA and 0.4 for NET-EN (unspecified dose interval).
Bigrigget
at
(1999, p.?l) state that Depo Provera is "... the most effective reversible contraceptive available", with a user failure rate approaching the method failure rate. The efficacy ofDMPA and NET-EN given every 8 weeks is comparable,however, since women on the NET-EN regimen have to return to the clinic every eight weeks (versus every 12 weeks with DMPA) for their next injection,the in-use failure rate for NET-EN may be higher.Conclusion
Whilst there are minor differences in published efficacy rates, depending on the study, timing of the first injection, the population, body weight, dosage regimen and provider training, the efficacy rate of both the IPCs is very high. The efficacy of 150mg DMPA given every 90 days and 200mg NET-EN given every 60 days are comparable. Because women using NET-EN have to return for their next dose earlier than DMP A users, the in- use failure rate for NET-EN may be higher.
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Table 1.1.2 Summary of findings on efficacy from relevant studies
Study Notes Measure DMPA NET-EN 200mg"
150mg* Regimen 1 Regimen 2
I
Regimen 3Pregnancy rate per 100 woman-years
1. Zanartu& Navarro, 1968 N/A N/A N=130
(NET-ENonly, fertile ~,Chile, N=130)
Pregnancy rate 2.3
(average observation per patient for 17.6 months)
2. Chinnatamby, 1971 N=5l5 N/A N/A N=520
(Comparative study,Ceylon - now Sri
Lanka,N=1035) Most NET-EN users who became Pregnancy rate at 15 months 0.4 2.3
pregnant,didsointhe 1stcourse of therapy
3. EI-Mahgoub& Karim, 1972 N/A N/A N/A N=171
("birth control clinic",NET-EN only,
Egypt (1968-1971),proven fertility,non- In some instances,delays between Pregnancy rate 0.0
breastfeeding, no hormonal contraceptive injections of95 daysoccurred history,N=17l)
4. SchwaIIie& Azenzo, 1973T N=3857 N/A N/A N/A
(Multi-centre, collaborative study, 1965-
1971,54investigators, DMPA only, Pregnancy rate:
healthy women, 54.7% were white, at 12 months 0.31
demonstrated fertility, N=3857) at 24 months 0.53
*
Given every 12 weeks or every 90 days# Regimen 1: Given every 60 days; Regimen 2:Given every 60 days or 8 weeks for six months and then every 12 weeks;Regimen 3: Given every 12 weeks.
v.w
Table 1.1.2 Continued
Study Notes Measure DMPA NET-EN 200mgll
(WHO=World Health Organization) 150mg* Regimen 1 Regimen 2 Regimen 3
Pregnancy rate per 100 woman-years
5. WHO, 1977t Study was to have lasted for 2 yrs, but N=846 N/A N/A N=832
(Randomised 10-centre comparative was terminated after ± 1 yr as NET-EN
trial,healthy non-breastfeeding ~of pregnancy rate exceeded the allowed Cumulative 12-month 0.7 ±004 3.6±0.7
demonstrated fertility, N=1678) maximum gross pregnancy rate per
100 woman-years Participating Centres: Alexandria, No pregnancies in Ibadan&Utrecht statistically significant Bahia-Salvador, Bangkok, Bombay,
Chandigarh, Ibadan, Ljubljana, 54% of pregnancies for NET-EN Manila,Utrecht, Lima observed in Bangkok&Chandigarh
75% of all conceptions with NET-EN estimated to have occurred during first injection period
Mean admission body wt. of NET-EN users who became pregnant
significantly lower
6. WHO, 1983t N-1587 N-789 N-796 N/A
(2 year multi-national comparative
0.6± 0.3
randomized trial, 13 centres, healthy Cumulative 12-month 0.1±0.1 OA±O.2
non-breastfeeding ~ N=31 72) pregnancy rate per 100
woman-years
Participating Centres: Alexandria, not statistic. significant
Bangkok, Ibadan, Karachi, Lusaka,
004± 0.3 004± 0.2 lA ± 0.6
Manila,Mexico City, Salvador, Cumulative 2-year
Santiago, Ljubljana, Luxembourg, pregnancy rate/lOO
Milan, Utrecht woman-years
not statistic.significant
*
Given every 12 weeks or every 90 days# Regimen 1: Given every 60 days; Regimen 2: Given every 60 days or 8 weeks for six months and then every 12 weeks; Regimen 3: Given every 12 weeks
t Additional information about the study design obtained from Kaunitz (1992).
Table 1.1.2 Continued
Study Notes Measure DMPA NET-EN 200mg"
150mg* Regimen 1 Regimen 2 Regimen 3
Pregnancy rate per 100 woman-years
7. Banerjeeet 011984 Speculated that the unexpectedly N/A N=1181 N=1207 N/A
(comparative clinical trial oftwo dosage high failure rates may be a result of
regimens of NET-EN,Indian ~, 16 lower body weights of Indian Method failure rates: 1.2 0.7
Human Reproductive Research Centres, women at 6 months
N=2388) not statistic. significant
Life-table reconstructed& day 1 set where dosage schedule was changed (Le. after the 4th injection) (statistic.Significant difJfound
at 12 months 0.0 1.1
at 18 months 0.2 2.1
at 24 months 0.2 6.0
8. Rahmanetat,1985
(field study in 6 clinics, NET-EN only, Bangladesh,N=913)
Cumulative pregnancy rate at 18months 0.4
*
Given every 12 weeks or every 90 days# Regimen 1: Given every 60 days; Regimen 2: Given every 60 days or 8 weeks for six months and then every 12 weeks;Regimen 3: Given every 12 weeks.
1.1.3 RETURN TO FERTILITY